US10160753B2 - Indazole compounds as IRAK4 inhibitors - Google Patents

Indazole compounds as IRAK4 inhibitors Download PDF

Info

Publication number
US10160753B2
US10160753B2 US15/110,309 US201515110309A US10160753B2 US 10160753 B2 US10160753 B2 US 10160753B2 US 201515110309 A US201515110309 A US 201515110309A US 10160753 B2 US10160753 B2 US 10160753B2
Authority
US
United States
Prior art keywords
indazol
methyl
oxazole
carboxamide
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US15/110,309
Other languages
English (en)
Other versions
US20160326151A1 (en
Inventor
Venkateshwar Rao GUMMADI
Susanta Samajdar
Ajay Gupta
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aurigene Oncology Ltd
Original Assignee
Aurigene Discovery Technologies Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=52462359&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US10160753(B2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Aurigene Discovery Technologies Ltd filed Critical Aurigene Discovery Technologies Ltd
Assigned to AURIGENE DISCOVERY TECHNOLOGIES LIMITED reassignment AURIGENE DISCOVERY TECHNOLOGIES LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GUMMADI, VENKATESHWAR RAO, GUPTA, AJAY, SAMAJDAR, SUSANTA
Publication of US20160326151A1 publication Critical patent/US20160326151A1/en
Application granted granted Critical
Publication of US10160753B2 publication Critical patent/US10160753B2/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/11—Esters of phosphoric acids with hydroxyalkyl compounds without further substituents on alkyl

Definitions

  • This invention relates to compounds useful for treatment of cancer and inflammatory diseases associated with Interleukin-1 Receptor Associated Kinase (IRAK) and more particularly compounds that modulate the function of IRAK-4.
  • IRAK Interleukin-1 Receptor Associated Kinase
  • the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of diseases associated with IRAK-4.
  • Interleukin-1 (IL-1) Receptor-Associated Kinase-4 (IRAK-4) is a serine/threonine kinase enzyme that plays an essential role in signal transduction by Toll/IL-1 receptors (TIRs).
  • TIRs Toll/IL-1 receptors
  • IRAK-1R interleukin-1 receptor
  • TLRs Toll-like receptors
  • IRAK-1, IRAK-2, IRAK-M IRAK-4.
  • IRAK proteins are characterized by a typical N-terminal death domain that mediates interaction with MyD88-family adaptor proteins and a centrally located kinase domain.
  • the IRAK proteins, as well as MyD88, have been shown to play a role in transducing signals other than those originating from IL-1R receptors, including signals triggered by activation of IL-18 receptors (Kanakaraj, et al. J. Exp. Med. 189(7), 1999, 1129-38) and LPS receptors (Yang, et al., J. Immunol. 163(2), 1999, 639-643).
  • IRAK-4 is considered to be the “master IRAK”.
  • IRAKs Under overexpression conditions, all IRAKs can mediate the activation of nuclear factor- ⁇ B (NF- ⁇ B) and stress-induced mitogen activated protein kinase (MAPK)-signaling cascades.
  • NF- ⁇ B nuclear factor- ⁇ B
  • MAPK mitogen activated protein kinase
  • IRAK-1 and IRAK-4 have been shown to have active kinase activity. While IRAK-1 kinase activity could be dispensable for its function in IL-1-induced NF- ⁇ B activation (Kanakaraj et al, J. Exp. Med. 187(12), 1998, 2073-2079) and (Li, et al. Mol. Cell. Biol.
  • IRAK-4 requires its kinase activity for signal transduction [(Li S, et al. Proc. Natl. Acad. Sci. USA 99(8), 2002, 5567-5572) and (Lye, E et al, J. Biol. Chem. 279(39); 2004, 40653-8)].
  • IRAK4 inhibitors Given the central role of IRAK4 in Toll-like/IL-1R signalling and immunological protection, IRAK4 inhibitors have been implicated as valuable therapeutics in inflammatory diseases, sepsis and autoimmune disorders (Wietek C, et al, Mol. Interv. 2: 2002, 212-215).
  • mice lacking IRAK-4 are viable and show complete abrogation of inflammatory cytokine production in response to IL-1, IL-18 or LPS (Suzuki et al. Nature, 416(6882), 2002, 750-756). Similarly, human patients lacking IRAK-4 are severely immunocompromised and are not responsive to these cytokines (Medvedev et al. J. Exp. Med., 198(4), 2003, 521-531 and Picard et al. Science 299(5615), 2003, 2076-2079). Knock-in mice containing inactive IRAK4 were completely resistant to lipopolysaccharide- and CpG-induced shock (Kim T W, et al. J. Exp.
  • IRAK4 KI Inactivation of IRAK4 kinase (IRAK4 KI) in mice leads to resistance to EAE due to reduction in infiltrating inflammatory cells into CNS and reduced antigen specific CD4+ T-cell mediated IL-17 production (Staschke et al. The Journal of Immunology, 183(1), 2009, 568-577).
  • IRAK-4 contains characteristic structural features of both serine/threonine and tyrosine kinases, as well as additional novel attributes, including the unique tyrosine gatekeeper residue.
  • Structural analysis of IRAK-4 revealed the underlying similarity with kinase family; ATP-binding cleft sandwiched between a bilobal arrangements.
  • the N-terminal lobe consists of mainly of a twisted five-stranded antiparallel beta-sheet and one alpha-helix, and the larger C-terminal lobe is predominantly alpha-helical.
  • the structure reveals a few unique features for IRAK-4 kinase, including an additional alpha-helix from the N-terminal extension in the N-terminal lobe, a longer loop between helices alpha-D and alpha-E, and a significantly moved helix alpha G as well as its adjoining loops.
  • the ATP-binding site in IRAK-4 has no deep pocket in the back but has a featured front pocket. This uniquely shaped binding pocket provides an excellent opportunity for designing IRAK-4 inhibitors.
  • IRAK-4 kinase inhibitors have generated several novel classes of protein binders which includes thiazole and pyridine amides (George M Buckley, et al. Bioorg. Med. Chem. Lett., 18(11), 2008, 3211-3214), aminobenzimidazoles (Powers J P, et al. Bioorg. Med. Chem. Lett., 16(11), 2006, 2842-2845), Imidazo[1,2-a] pyridines (Buckley G M, et al. Bioorg. Med. Chem. Lett. 18(12), 2008, 3656-3660) and (Buckley G M, et al. Bioorg. Med. Chem. Lett.
  • kinase inhibitors including multikinase inhibitors, which may be further useful in treatment of disorders owing to variations in various kinases activity and possessing broader role. They may also be useful as part of other therapeutic regimens for the treatment of disorders, alone or in combination with protein kinase compounds well known by the one skilled in the art.
  • One objective herein is to provide indazole compounds of formula (I) as kinase inhibitors, particularly IRAK4 inhibitors.
  • Another objective is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I) or pharmaceutically acceptable salt or stereoisomer thereof, and atleast one pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent.
  • Yet another objective is to provide a use of Indazole compound of formula (I) or pharmaceutically acceptable salt or stereoisomer thereof for the treatment and/or prevention of diseases or disorders, in particular their use in diseases or disorder mediated by kinase enzyme, more particularly IRAK4 enzyme.
  • Ring Z 1 is an optionally substituted heteroaryl
  • Ring Z 2 is a optionally substituted heterocycloalkyl, optionally substituted heteroaryl or a direct bond;
  • R 1 is alkyl, cyano, —NR a R b , or optionally substituted groups selected from cycloalkyl, aryl or heterocyclyl; wherein the substituent, at each occurrence, independently is alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, —OCO—CH 2 —O-alkyl, —OP(O)(O-alkyl) 2 or —CH 2 —OP(O)(O-alkyl) 2 ;
  • R 2 at each occurrence, independently is an optionally substituted group selected from alkyl or cycloalkyl; wherein the substituent, at each occurrence, is independently halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl or haloalkoxy;
  • R 3 at each occurrence, independently is hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, —NR a R b , hydroxyl or hydroxyalkyl;
  • R a is hydrogen or alkyl
  • R b is hydrogen, alkyl, acyl, hydroxyalkyl, —SO 2 -alkyl or optionally substituted cycloalkyl;
  • ‘m’ and ‘n’ are independently 1 or 2.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, and atleast one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the invention relates to the use of indazole compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, including mixtures thereof in all ratios as a medicament, by inhibiting IRAK or IRAK4 other related kinases.
  • the compound of formula (I) of the present invention possess therapeutic role of inhibiting IRAK or IRAK4 related kinases useful in the area of diseases and/or disorders include, but are not limited to cancers, allergic diseases and/or disorders, autoimmune diseases and/or disorders, inflammatory diseases and/or disorder and/or conditions associated with inflammation and pain, proliferative diseases, hematopoietic disorders, hematological malignancies, bone disorders, fibrosis diseases and/or disorders, metabolic disorders and/or diseases, muscle diseases and/or disorders respiratory diseases and/or disorders, pulmonary disorders, genetic developmental diseases and/or disorders, neurological and neurodegenerative diseases and/or disorders, chronic inflammatory demyelinating neuropathies, cardiovascular, vascular or heart diseases and/or disorders, ophthalmic/ocular diseases and/or disorders, wound repair, infection and viral diseases. Therefore, inhibition of one or more of kinases would have multiple therapeutic indications.
  • the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not.
  • “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.
  • substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, —OCO—CH 2 —O-alkyl, —OP(O)(O-alkyl) 2 or —CH 2 —OP(O)(O-alkyl) 2 .
  • “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.
  • alkyl refers to saturated aliphatic groups, including but not limited to C 1 -C 10 straight-chain alkyl groups or C 1 -C 10 branched-chain alkyl groups.
  • the “alkyl” group refers to C 1 -C 6 straight-chain alkyl groups or C 1 -C 6 branched-chain alkyl groups.
  • the “alkyl” group refers to C 1 -C 4 straight-chain alkyl groups or C 1 -C 4 branched-chain alkyl groups.
  • alkyl examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl and the like.
  • the “alkyl” group may be optionally substituted.
  • acyl refers to a group R—CO— wherein R is an alkyl group defined above.
  • examples of ‘acyl’ groups are, but not limited to, CH 3 CO—, CH 3 CH 2 CO—, CH 3 CH 2 CH 2 CO— or (CH 3 ) 2 CHCO—.
  • alkoxy refers to a straight or branched, saturated aliphatic C 1 -C 10 hydrocarbon radical bonded to an oxygen atom that is attached to a core structure.
  • alkoxy groups Preferably, alkoxy groups have one to six carbon atoms. Examples of alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methyl butoxy and the like.
  • haloalkyl refers to alkyl group (as defined above) is substituted with one or more halogens.
  • a monohaloalkyl radical for example, may have a chlorine, bromine, iodine or fluorine atom.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same or different halogen atoms.
  • haloalkyl examples include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl and the like.
  • haloalkoxy refers to radicals wherein one or more of the hydrogen atoms of the alkoxy group are substituted with one or more halogens.
  • Representative examples of “haloalkoxy” groups include, but not limited to, difluoromethoxy (—OCHF 2 ), trifluoromethoxy (—OCF 3 ) or trifluoroethoxy (—OCH 2 CF 3 ).
  • aryl alone or in combination with other term(s) means a 6- to 10-membered carbocyclic aromatic system containing one or two rings wherein such rings may be fused.
  • fused means that the second ring is attached or formed by having two adjacent atoms in common with the first ring.
  • fused is equivalent to the term “condensed”. Examples of aryl groups include but are not limited to phenyl, naphthyl or indanyl and the like. Unless otherwise specified, all aryl groups described herein may be optionally substituted.
  • amino refers to an —NH 2 group.
  • aminoalkyl refers to an amino group, as defined above, in which one or two hydrogen atoms are substituted with alkyl group.
  • nitro refers to an —NO 2 group.
  • alkylamino and cycloalkylamino refer to an —N-group, wherein nitrogen atom of said group being attached to alkyl or cycloalkyl respectively.
  • Representative examples of an “Alkylamino” and “Cycloalkylamino” groups include, but are not limited to —NHCH 3 and —NH-cyclopropyl.
  • An amino group can be optionally substituted with one or more of the suitable groups.
  • cycloalkyl alone or in combination with other term(s) means C 3 -C 10 saturated cyclic hydrocarbon ring.
  • a cycloalkyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms. Examples of single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • a cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclyls.
  • cyano refers to —CN group.
  • hydroxy or “hydroxyl” refers to —OH group.
  • hydroxyalkyl or “hydroxylalkyl” means alkyl substituted with one or more hydroxyl groups, wherein the alkyl groups are as defined above.
  • examples of “hydroxyalkyl” include but are not limited to hydroxymethyl, hydroxyethyl, hydroxypropyl, propan-2-ol and the like.
  • halo or halogen alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine.
  • heterocyclyl includes definitions of “heterocycloalkyl” and “heteroaryl”.
  • heterocycloalkyl refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system of 3 to 15 member having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O) 2 , NH or C(O) with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • heterocycloalkyl examples include, but are not limited to azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, 2-aza-bicyclo[2.2.2]octanyl, azocinyl, chromanyl, xanthenyl and N-oxides thereof
  • heterocycloalkyl refers to 5- to 6-membered ring selected from the group consisting of azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl and N-oxides thereof.
  • heterocycloalkyl includes azetidinyl, pyrrolidinyl, morpholinyl and piperidinyl. All heterocycloalkyl are optionally substituted by one or more aforesaid groups.
  • heteroaryl refers to an aromatic heterocyclic ring system containing 5 to 20 ring atoms, suitably 5 to 10 ring atoms, which may be a single ring (monocyclic) or multiple rings (bicyclic, tricyclic or polycyclic) fused together or linked covalently.
  • heteroaryl is a 5- to 6-membered ring.
  • the rings may contain from 1 to 4 heteroatoms selected from N, O and S, wherein the N or S atom is optionally oxidized or the N atom is optionally quarternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure.
  • heteroaryl examples include, but are not limited to: furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalin
  • heteroaryl refers to 5- to 6-membered ring selected from the group consisting of furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. More preferably, pyrazolyl, pyridyl, oxazolyl and furanyl. All heteroaryls are optionally substituted by one or more aforesaid groups.
  • the term ‘compound(s)’ comprises the compounds disclosed in the present invention.
  • phrases “pharmaceutically acceptable” refers to compounds or compositions that are physiologically tolerable and do not typically produce allergic or similar untoward reaction, including but not limited to gastric upset or dizziness when administered to mammal.
  • pharmaceutically acceptable salt refers to a product obtained by reaction of the compound of the present invention with a suitable acid or a base.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts;
  • suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts
  • suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate
  • Certain compounds of the invention can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin.
  • Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc, salts.
  • stereoisomer is a term used for all isomers of individual compounds of compound of formula (I) that differ only in the orientation of their atoms in space.
  • stereoisomer includes mirror image isomers (enantiomers) of compound of formula (I), mixtures of mirror image isomers (racemates, racemic mixtures) of compound of formula (I), geometric (cis/trans or E/Z, R/S) isomers of compound of formula (I) and isomers of compound of formula (I) with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • composition refers to a composition(s) containing a therapeutically effective amount of at least one compound of formula (I) or its pharmaceutically acceptable salt; and a conventional pharmaceutically acceptable carrier.
  • composition(s) of the present invention can be administered orally, for example in the form of tablets, coated tablets, pills, capsules, granules or elixirs. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermals, in the form of patches, or in other ways, for example in the form of aerosols or nasal sprays.
  • the pharmaceutical composition(s) usually contain(s) about 1% to 99%, for example, about 5% to 75%, or from about 10% to about 30% by weight of the compound of formula (I) or pharmaceutically acceptable salts thereof.
  • the amount of the compound of formula (I) or pharmaceutically acceptable salts thereof in the pharmaceutical composition(s) can range from about 1 mg to about 1000 mg or from about 2.5 mg to about 500 mg or from about 5 mg to about 250 mg or in any range falling within the broader range of 1 mg to 1000 mg or higher or lower than the afore mentioned range.
  • the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents.
  • the compositions also can include stabilizers and preservatives.
  • the examples of carriers, stabilizers and adjuvant are mentioned in literature like, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. [1975].
  • treatment means any treatment of a disease in a mammal, including: (a) Inhibiting the disease, i.e., slowing or arresting the development of clinical symptoms; and/or (b) Relieving the disease, i.e., causing the regression of clinical symptoms and/or (c) alleviating or abrogating a disease and/or its attendant symptoms.
  • prevent refers to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease.
  • prevent also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
  • the term “subject” refers to an animal, preferably a mammal, and most preferably a human.
  • terapéuticaally effective amount refers to an amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof; or a composition comprising the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, effective in producing the desired therapeutic response in a particular patient suffering from a disease or disorder mediated by kinase enzymes, particularly IRAK or IRAK4 enzyme.
  • the term “therapeutically effective amount” includes the amount of the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, when administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject.
  • the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment can also be considered.
  • the therapeutically effective amount of the compound or composition will be varied with the particular condition being treated, the severity of the condition being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the age and physical condition of the end user, the specific compound or composition employed the particular pharmaceutically acceptable carrier utilized.
  • the present invention provides the compound of formula (I)
  • Ring Z 1 is an optionally substituted heteroaryl
  • Ring Z 2 is an optionally substituted heterocycloalkyl, optionally substituted heteroaryl or a direct bond;
  • R 1 is alkyl, cyano, —NR a R b , or optionally substituted groups selected from cycloalkyl, aryl or heterocyclyl; wherein the substituent, at each occurrence, independently is alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, —OCO—CH 2 —O-alkyl, —OP(O)(O-alkyl) 2 or —CH 2 —OP(O)(O-alkyl) 2 ;
  • R 2 at each occurrence, independently is an optionally substituted group selected from alkyl or cycloalkyl; wherein the substituent, at each occurrence, is independently halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl or haloalkoxy;
  • R 3 at each occurrence, independently is hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, —NR a R b , hydroxyl or hydroxyalkyl;
  • R a is hydrogen or alkyl
  • R b is hydrogen, alkyl, acyl, hydroxyalkyl, —SO 2 -alkyl or optionally substituted cycloalkyl;
  • ‘m’ and ‘n’ are independently 1 or 2.
  • the present invention provides the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein, Ring Z 1 is a 5- or 6-membered optionally substituted heteroaryl.
  • the present invention provides the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein Ring Z 1 is an optionally substituted heteroaryl; wherein the optional substituent is alkyl;
  • Ring Z 1 is selected from the group consisting of tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl and pyrazolyl.
  • Ring Z 1 is selected from the group consisting of pyridyl, oxazolyl and furanyl; wherein the pyridyl group is optionally substituted with alkyl; in particular alkyl is methyl.
  • Ring Z 2 is a 5- or 6-membered heteroaryl selected from tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl or pyrazolyl.
  • Ring Z 2 is a 5- or 6-membered heteroaryl selected from tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl or pyr
  • Ring Z 2 is a 5- or 6-membered heterocycloalkyl selected from azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl or 1,4-dioxanyl.
  • the compound of formula (I) is compound of formula (IA)
  • the compound of formula (I) is compound of formula (IB)
  • the compound of formula (I) is compound of formula (IC)
  • compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted heterocyclyl; wherein the substituent is halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, —OCO—CH 2 —O-alkyl, —OP(O)(O-alkyl) 2 or —CH 2 —OP(O)(O-alkyl) 2 .
  • R 1 is optionally substituted azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl or azepanyl; wherein the substituent is amino, halogen, hydroxyl, hydroxyalkyl, aminoalkyl, —OCO—CH 2 —O-alkyl, —OP(O)(O-alkyl) 2 or —CH 2 —OP(O)(O-alkyl) 2 .
  • compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted piperidinyl; wherein the substituent is hydroxyl.
  • compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted phenyl; wherein the substituent is halogen.
  • compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R 1 is cyclopropyl or cyclohexyl.
  • R 1 is —NR a R b ;
  • R a is hydrogen;
  • R b is optionally substituted cycloalkyl; wherein the substituent is hydroxyl.
  • compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R 2 is optionally substituted alkyl; wherein substituent is alkoxy.
  • compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R 3 is hydrogen, halogen, alkyl, alkoxy, —NR a R b , hydroxyl or hydroxyalkyl; R a is hydrogen or alkyl; and R b is hydrogen, alkyl, acyl, hydroxyalkyl or —SO 2 -alkyl.
  • Ring Z 1 is optionally substituted pyridyl
  • Ring Z 2 is pyridyl, pyrazolyl, pyrrolidinyl or direct bond
  • R 1 is an optionally substituted group selected from cyclopropyl, piperidinyl, morpholinyl or pyrrolidinyl
  • R 2 is optionally substituted alkyl or cycloalkyl
  • R 3 is hydrogen, halogen, alkyl, alkoxy, —NR a R b , hydroxyl or hydroxyalkyl
  • R a is hydrogen or alkyl
  • R b is hydrogen or hydroxyalkyl.
  • Ring Z 1 is oxazolyl
  • Ring Z 2 is pyridyl, pyrazolyl or pyrrolidinyl
  • R 1 is cyano, —NR a R b , or an optionally substituted group selected from cyclopropyl, cyclohexyl, phenyl, azetidinyl, piperidinyl, morpholinyl or pyrrolidinyl
  • R 2 is optionally substituted alkyl or cycloalkyl
  • R 3 is hydrogen, halogen, alkyl, alkoxy, —NR a R b , hydroxyl or hydroxyalkyl
  • R a is hydrogen or alkyl
  • R b is hydrogen, alkyl, acyl, hydroxyalkyl, —SO 2 -alkyl or optionally substituted cycloalkyl.
  • R 3 is —NR a R b ;
  • R a is hydrogen or alkyl; and
  • R b is hydrogen, alkyl, acyl, hydroxyalkyl, —SO 2 -alkyl or optionally substituted cycloalkyl; wherein the optional substituent is hydroxyl;
  • the present invention relates to a process for preparing indazole compound of formula (I).
  • the present invention relates to a pharmaceutical composition, comprising at least one compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present invention relates to a compound or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament.
  • the present invention relates to a method of treating IRAK4 mediated disorders or diseases or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (I) or (IA) or (IB) or (IC).
  • the IRAK-mediated disorder or disease or condition is selected from the group consisting of a cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder and a CNS disorder.
  • the IRAK-mediated disorder or disease or condition is selected from the group consisting of a cancer, an inflammatory disorder, a an autoimmune disease, metabolic disorder, a hereditary disorder, a hormone-related disease, immunodeficiency disorders, a condition associated with cell death, a destructive bone disorder, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation and a cardiovascular disorder.
  • the cancer or proliferative disorder is selected the group consisting of a solid tumor, benign or malignant tumor, carcinoma of the brain, kidney, liver, stomach, vagina, ovaries, gastric tumors, breast, bladder colon, prostate, pancreas, lung, cervix, testis, skin, bone or thyroid; sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, a mammary carcinoma, follicular carcinoma, papillary carcinoma, seminoma, melanoma; hematological malignancies selected from leuk
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy and graft versus host disease.
  • the inflammatory disorder is selected from the group consisting of ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, allergic rhinitis, autoimmune hematological disorders (e.g.
  • hemolytic anemia aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia
  • systemic lupus erythematosus rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (e.g.
  • idiopathic nephrotic syndrome or minimal change nephropathy including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis renal disease, glaucoma, retinal disease, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, fibrositis, gastritis, gastroenteritis, nasal sinusitis, ocular allergy, silica induced diseases, chronic obstructive pulmonary disease (COPD), cyst
  • a compound of formula (I) or (IA) or (IB) or (IC) or a pharmaceutically acceptable salt or a stereoisomer thereof for use for the treatment of a cancer, an inflammatory disorder, a an autoimmune disease, metabolic disorder, a hereditary disorder, a hormone-related disease, immunodeficiency disorders, a condition associated with cell death, a destructive bone disorder, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation and a cardiovascular disorder.
  • An embodiment of the present invention provides the IRAK4 inhibitor compounds according to of formula (I) may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional compounds of the present invention claimed herein. All temperatures are in degrees Celsius (° C.) unless otherwise noted.
  • the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
  • Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2 H (“D”), 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 15 F, 36 Cl, 123 I and 125 I.
  • Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • substitution patterns and substituents on the compounds of the present invention can be selected by an ordinary skilled person in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent itself is substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, as long as a stable structure is resulted.
  • the first general approach for the synthesis of compounds of general formula (I) is depicted in scheme-1.
  • Compound of formula (ii) can be obtained from compound of formula (i) or (xiii) by coupling with compounds including appropriate boronic acids and amines.
  • Compound of formula (iii) can be obtained by the alkylation of compound of formula (ii) by using appropriate bases like potassium carbonate, or sodium hydride and suitable alkyl halides.
  • Compound of formula (iii) can be reduced with suitable reducing reagents like Fe powder and HCl to give compound of formula (iv) which on amide coupling with a suitable acid of compound of formula (v) by using standard amide coupling reagent known in the literature can give compound of formula (I).
  • a compound of formula (xi) can be nitrated by potassium nitrate and sulphuric acid to give compound of formula (xii) which on further reaction with hydrazine at certain temperature can give compound of formula (xiii).
  • Step 1 Preparation of methyl 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinate
  • methyl 6-bromopicolinate (900 mg, 4.166 mmol) was coupled with 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.39 g, 5 mmol) using sodium carbonate (1.324 g, 12.49 mmol) and Pd(PPh 3 ) 2 Cl 2 (339 mg, 0.416 mmol) in 1,2-dimethoxyethane (10 mL) and water (2 mL) and purged argon for 10 min, and heated at 95° C. overnight to get the crude product.
  • methyl 6-bromopicolinate (3.5 g, 16.28 mmol) was coupled with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.06 g, 19.53 mmol) using sodium carbonate (5.177 g, 48.846 mmol) and Pd(dppf)Cl 2 (1.328 g, 1.628 mmol) in 1,2-dimethoxyethane (20 mL) to get the crude product.
  • Step 1 Preparation of ethyl 2-(6-fluoropyridin-3-yl)oxazole-4-carboxylate
  • step 2 of intermediate 2 ethyl 2-(6-fluoropyridin-3-yl)oxazole-4-carboxylate (300 mg, 0.127 mmol) was hydrolyzed using lithium hydroxide (160 mg, 3.91 mmol) in THF/methanol/water (5/1/2 mL) at RT for 2 h to obtain the title compound (160 mg, 57.3%).
  • Step 1 Preparation of ethyl 2-(2-methylpyridin-3-yl)oxazole-4-carboxylate
  • step 2 of intermediate 2 ethyl 2-(2-methylpyridin-3-yl)oxazole-4-carboxylate (1 g, 4.3 mmol) was hydrolyzed using lithium hydroxide (542 mg, 12.9 mmol) in THF/water (25/4 mL) at RT for 2 h to obtain the title compound (550 mg, 62.5%).
  • Step 1 Preparation of ethyl 2-(2-fluoropyridin-3-yl)oxazole-4-carboxylate
  • step 2 of intermediate 2 ethyl 2-(2-fluoropyridin-3-yl)oxazole-4-carboxylate (400 mg, 1.69 mmol) was hydrolyzed using lithium hydroxide (213 mg, 5.07 mmol) in THF/water (10/2 mL) at RT for 2 h to obtain the title compound (250 mg, 71.6%).
  • Step 2 Preparation of (R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol
  • Step 1 Preparation of ethyl (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylate
  • Step 2 Preparation of (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylic acid
  • step 2 of intermediate 2 ethyl (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylate (170 mg, 0.5224 mmol) was hydrolyzed using lithium hydroxide (33 mg, 0.7837 mmol) in THF/methanol/water (10/1/2 mL) at RT for 12 h to obtain the title compound (150 mg, 96.77%).
  • LCMS: m/z 242.0 (M-t-butyl+1) + .
  • Step 2 Preparation of (S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol
  • Step 1 Preparation of ethyl (S)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxylate
  • Step 2 Preparation of ethyl (S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylate
  • Step 3 Preparation of(S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylic acid
  • step 2 of intermediate 2 ethyl (S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylate (520 mg, 1.5294 mmol) was hydrolyzed using lithium hydroxide (97 mg, 2.2941 mmol) in THF/methanol/water (10/5/5 mL) at RT for 2 h to obtain the title compound (350 mg, 73.37%).
  • Step 1 Preparation of ethyl 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxylate
  • step 2 of intermediate 2 ethyl 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxylate (200 mg, 0.784 mmol) was hydrolyzed using lithium hydroxide (50 mg, 1.176 mmol) in THF/methanol/water (5/2/1 mL) at RT for 1 h to obtain the title compound (206 mg, 100%).
  • Step-1 Preparation of 2-fluoro-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine
  • Step-2 Synthesis of methyl 2′-fluoro-[2, 3′-bipyridine]-6-carboxylate
  • methyl 2′-fluoro-[2, 3′-bipyridine]-6-carboxylate (1.38 g, 5.97 mmol) was hydrolysed using lithium hydroxide (502 mg, 11.95 mmol) in THF/methanol/water (10/10/10 mL) at RT for 12 h to obtain the title compound (643 mg, 49%).
  • methyl 5-bromofuran-2-carboxylate (214 mg, 1.0406 mmol) was coupled with 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (340 mg, 1.561 mmol) using potassium carbonate (288 mg, 2.08 mmol) TBAB (50 mg, 0.156 mmol) and Pd(dppf)Cl 2 (54 mg, 0.078 mmol) in dioxane/water (10/3 mL) to get the crude product.
  • methyl 5-(2-methylpyridin-4-yl)furan-2-carboxylate 300 mg, 1.38 mmol was hydrolyzed using lithium hydroxide (116 mg, 2.76 mmol) in THF/methanol/water (10/5/5 mL) at 50° C. for 0.25 h to obtain the desired compound (260 mg, 92.8%).
  • LCMS: m/z 204.1 (M+1) + .
  • Step 1 Preparation of ethyl 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylate
  • N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (2.78 g, 10.04 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (1 g, 7.09 mmol) using sodium carbonate (106 mg, 21.2 mmol) and Pd(dppf)Cl 2 (259 mg, 0.354 mmol) in 1,2-dimethoxyethane/water (30/5 mL) to get the crude product.
  • step 2 of intermediate 2 ethyl 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylate (500 mg, 1.81 mmol) was hydrolyzed using lithium hydroxide (84 mg, 2 mmol) in THF/methanol/water (10/1/5 mL) at RT for 4 h to obtain the title compound (360 mg, 81.08%).
  • step 2 of intermediate 2 ethyl 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylate (product of step 1 of intermediate 13) (900 mg, 3.27 mmol) was hydrolyzed using lithium hydroxide (329 mg, 7.85 mmol) in THF/methanol/water (30/1/5 mL) at RT for 4 h to obtain the title compound (750 mg, 96%).
  • Step 1 Preparation of ethyl 2-(2-fluoropyridin-4-yl)oxazole-4-carboxylate
  • step 2 of intermediate 2 ethyl 2-(2-fluoropyridin-4-yl)oxazole-4-carboxylate (100 mg, 0.349 mmol) was hydrolyzed using lithium hydroxide (80 mg, 1.398 mmol) in water (2 mL) at 70° C. for 14 h to obtain the crude title compound (80 mg).
  • Step 1 Preparation of ethyl 2-(2,6-dimethylpyridin-4-yl)oxazole-4-carboxylate
  • step 2 of intermediate 2 ethyl 2-(2,6-dimethylpyridin-4-yl)oxazole-4-carboxylate (650 mg, 2.642 mmol) was hydrolyzed using lithium hydroxide (216 mg, 5.28 mmol) in THF/water (4/2 mL) at RT for 2 h to obtain the title compound (400 mg, 69.8%).
  • Step-1 Preparation of methyl 2-(2-(N-methylacetamido) pyridin-4-yl)oxazole-4-carboxylate
  • step-1 of intermediate 13 2-(2-acetamidopyridin-4-yl) oxazole-4-carboxylate (step-1 of intermediate 13) (500 mg 1.8 mmol) in DMF (5 ml) at 0° C. slowly added sodium hydride 60% (174 mg 3.60 mmol) and methyl iodide (510 mg 3.60 mmol) and allowed to come to RT stirred at RT for one hour, quenched the reaction mixture by aqueous NH 4 Cl and extracted the compound to ethyl acetate dried and concentrated it, purified by column chromatography in 50% ethyl acetate in hexane to obtain the title compound (400 mg). LCMS: 276.3 (M+1) + .
  • Step-2 Preparation of 2-(2-(methyl amino) pyridin-4-yl) oxazole-4-carboxylic acid
  • Step-1 Preparation of methyl 2-(2-aminopyridin-4-yl)oxazole-4-carboxylate
  • step-1 of intermediate 13 A solution of 2-(2-acetamidopyridin-4-yl) oxazole-4-carboxylate (step-1 of intermediate 13) (1.2 g 4.3 mmol) in methanol (10 ml) at 0° C. added Conc. HCl (5 ml) stirred at 65° C. for 2 hours. The reaction mixture was concentrated, basified with NaHCO 3 solution, extracted to ethyl acetate and concentrated under reduced pressure, to obtain the title compound (950 mg).
  • Step-2 Preparation of methyl 2-(2-(methylsulfonamido) pyridin-4-yl) oxazole-4-carboxylate
  • Step-3 Preparation of 2-(2-(methylsulfonamido) pyridin-4-yl) oxazole-4-carboxylic acid
  • Step-5 Synthesis of 2-methyl-5-nitro-6-(piperidin-1-yl)-2H-indazole and 1-methyl-5-nitro-6-(piperidin-1-yl)-1H-indazole
  • Step-7 Synthesis of N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide
  • reaction mixture was diluted with EtOAc, washed with brine and dried over anhydrous Na 2 SO 4 . After concentration under reduced pressure, the residue was purified by flash chromatography (CH 2 Cl 2 :MeOH; 98.5:1.5) to give the title compound (0.090 g, 47%) as a brown solid.
  • Step-8 Synthesis of N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl) picolinamide
  • N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl) picolinamide (90 mg, 0.185 mmol) was dissolved in DCM (10 mL). To this solution ether-HCl (10 mL) was added and stirred at room temperature for 3 h. After completion of reaction, excess of solvent was removed under reduced pressure, basified with saturated sodium carbonate solution and diluted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous Na 2 SO 4 . After concentration, the residue was purified by column chromatography (CH 2 Cl 2 : MeOH; 98:2) to give the title compound (25 mg, 34%) as off-white solid.
  • Step-1 Synthesis of 1-methyl-6-(piperidin-1-yl)-1H-indazol-5-amine 1-methyl-5-nitro-6-(piperidin-1-yl)-1H-indazole (0.215 g, 1.5 mmol) (product of step 5 in example 1 (Isomer B)) was dissolved in ethanol (15 mL). To this solution iron powder (0.463 g, 8.26 mmol) and 0.2 ml of HCl were added at 0° C. and the reaction mixture was refluxed for 1 h. After completion of reaction, reaction mixture was cooled to room temperature and diluted with ethyl acetate and filtered through Celite®.
  • Step-2 Synthesis of N-(1-methyl-6-(piperidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl) oxazole-4-carboxamide
  • Step-1 Synthesis of 2-cyclopentyl-5-nitro-6-(piperidin-1-yl)-2H-indazole and 1-cyclopentyl-5-nitro-6-(piperidin-1-yl)-1H-indazole
  • Step-2 Synthesis of 2-cyclopentyl-6-(piperidin-1-yl)-2H-indazol-5-amine
  • Step-3 Synthesis of N-(2-cyclopentyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl) oxazole-4-carboxamide
  • Step-3 Synthesis of 6-bromo-2-cyclopentyl-5-nitro-2H-indazole (Isomer A) and 6-bromo-1-cyclopentyl-5-nitro-1H-indazole (Isomer B)
  • Step-6 Synthesis of N-(6-cyano-2-cyclopentyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl) oxazole-4-carboxamide
  • reaction mixture was diluted with ethyl acetate, washed with water followed by brine and the organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude compound.
  • the crude material was purified by preparative HPLC to give the title compound (0.006 g, 5.5%) as a brown solid.
  • Step-3 Synthesis of N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl) oxazole-4-carboxamide
  • reaction mixture was diluted with ethyl acetate, washed with water followed by brine and the organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude compound.
  • the crude material was purified by flash chromatography (CH 2 Cl 2 :MeOH; 99:1) to give the title compound (25 mg, 11%) as a brown solid.
  • Step-1 Synthesis of N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide
  • reaction mixture was diluted with ethyl acetate, washed with water followed by brine, the organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude compound.
  • the crude material was purified by flash chromatography (CH 2 Cl 2 :MeOH; 99:1) to give the title compound (0.100 g, 53%) as a off-white solid.
  • Step-2 Synthesis of N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl) picolinamide
  • N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl) picolinamide (0.100 g, 0.195 mmol) was dissolved in DCM (10 mL). To this solution ether-HCl (1 mL) was added and stirring was continued at room temperature for 12 h. The reaction mixture was cooled to 0° C. and basified with saturated sodium carbonate solution followed by extraction with ethyl acetate. The organic layer was washed with water followed by brine and dried over anhydrous Na 2 SO 4 . The residue was purified by column chromatography (CH 2 Cl 2 :MeOH; 98:2) to give the title compound (6 mg, 7.5%) as an off-white solid.
  • Step-1 Synthesis of 2-cyclopentyl-6-fluoro-5-nitro-2H-indazole and 1-cyclopentyl-6-fluoro-5-nitro-1H-indazole
  • Step-2 Synthesis of 4-(2-cyclopentyl-5-nitro-2H-indazol-6-yl) morpholine
  • 6-fluoro-2-cyclopentyl-5-nitro-2H-indazole (2 g, 1.61 mmol) was dissolved in morpholine (20 mL) and heated at 120° C. for 12 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (CH 2 Cl 2 :MeOH; 95:5) to give the title compound (0.4 g, 19%) as a brown semi solid.
  • Step-4 Synthesis of N-(2-cyclopentyl-6-morpholino-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl) oxazole-4-carboxamide
  • reaction mixture was diluted with ethyl acetate, washed with water followed by brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude compound.
  • the crude material was purified by preparative HPLC to give the title compound (30 mg, 21%) as a brown solid.
  • Step-1 Synthesis of tert-butyl (5-bromopyridin-2-yl) carbamate
  • Step-2 Synthesis of tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) carbamate
  • Step-3 Synthesis of methyl 6′-((tert-butoxycarbonyl) amino)-[2,3′-bipyridine]-6-carboxylate
  • tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl) carbamate (0.940 g, 2.93 mmol), 2M Na 2 CO 3 (0.757 g, 7.14 mmol) in 4 mL H 2 O and the corresponding methyl 6-bromopicolinate (0.633 g, 2.93 mmol) and Pd(dppf)Cl 2 (0.143 g, 0.175 mmol) are dissolved in DME (10 mL) and heated at 90° C. for 1 h. The mixture was evaporated and the residue was purified by silica gel flash chromatography.
  • Step-4 Synthesis of 6′-((tert-butoxycarbonyl) amino)-[2,3′-bipyridine]-6-carboxylic acid
  • Step-5 Synthesis of 6′-amino-N-(2-cyclopentyl-6-morpholino-2H-indazol-5-yl)-[2,3′-bipyridine]-6-carboxamide 2,2,2-trifluoroacetate
  • reaction mixture was diluted with EtOAc, washed with water followed by brine and the organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude compound.
  • the crude product is treated with TFA to deprotect Boc group at RT in DCM.
  • the crude material was purified by preparative HPLC using mobile phase-A: 0.1% TFA (aq), mobile phase-B: acetonitrile to give the title compound (0.034 g, 22%) as a brown solid.
  • 6-chloro-5-nitro-2H-indazole 500 mg, 2.55 mmol was methylated using sodium hydride (220 mg, 5.35 mmol and methyl iodide (1.44 g, 10.70 mmol) in THF to get the crude product. This was purified by silica gel column chromatography and elution with DCM gave the title compound (236 mg, 44%). LCMS: 212.2 (M+1) + .
  • 6-chloro-2-methyl-5-nitro-2H-indazole 35 mg, 0.142 mmol was coupled with (3-fluorophenyl)boronic acid (30 mg, 0.213 mmol) using Pd 2 (OAc) 2 (3 mg, 0.0106 mmol), potassium carbonate (59 mg, 0.426 mmol) and tricyclohexyl phosphine (6 mg, 0.0213 mmol) in toluene:H 2 O (17 mL, 10:7) at 100° C. for 10 h to obtain desired compound (21 mg, 52%).
  • Step-5 Synthesis of N-(6-(3-fluorophenyl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • 6-(3-fluorophenyl)-2-methyl-2H-indazol-5-amine 127 mg, 0.622 mmol
  • 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid 150 mg, 0.622 mmol
  • EDCI.HCl 178 mg, 0.931 mmol
  • HOBt 84 mg, 0.622 mmol
  • DIPEA 321 mg, 2.48 mmol
  • Step-1 Synthesis of 6-bromo-2-methyl-5-nitro-2H-indazole and 6-bromo-1-methyl-5-nitro-1H-indazole
  • 6-bromo-5-nitro-1H-indazole product of step 2 of example 5
  • THF 25 mL
  • 6-bromo-2-methyl-5-nitro-2H-indazole 100 mg, 0.390 mmol was coupled with 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (97 mg, 0.465 mmol) using Pd(dppf)Cl 2 .DCM (16 mg, 0.0195 mmol) and potassium carbonate (107 mg, 0.781 mmol) in 1,4-dioxane/H 2 O (6/2 mL) at 90° C. for 5 h to obtain desired compound (21 mg, 52%).
  • Step-4 Synthesis of N-(6-cyclohexyl-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride
  • 6-cyclohexyl-2-methyl-2H-indazol-5-amine 200 mg, 0.873 mmol
  • 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid 178 mg, 0.873 mmol
  • EDCI.HCl 250 mg, 0.131 mmol
  • HOBt 123 mg, 0.917 mmol
  • DIPEA 337 mg, 2.62 mmol
  • DMF 8 mL
  • Step-2 Synthesis of 6′-fluoro-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-[2,3′-bipyridine]-6-carboxamide hydrochloride
  • 6-bromo-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide (100 mg, 0.2413 mmol) was coupled with (6-fluoropyridin-3-yl)boronic acid (51 mg, 0.362 mmol) using Pd(dppf)Cl 2 (9 mg, 0.0120 mmol) and sodium carbonate (77 mg, 0.7241 mmol) in DME/H 2 O (5/2 mL) at 90° C. for 12 h to obtain crude product. This was purified by prep HPLC and treated with ether HCl to get the title compound (70 mg, 62.50%).
  • Step-1 Synthesis of N-(6-cyclohexyl-2-methyl-2H-indazol-5-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide
  • Step-2 Synthesis of N-(6-cyclohexyl-2-methyl-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)picolinamide hydrochloride
  • N-(6-cyclohexyl-2-methyl-2H-indazol-5-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide 120 mg, 0.2476 mmol was deprotected using ether HCl (0.5 mL) in DCM (10 mL) to get the title compound (80 mg, 81%).
  • Step-3 Synthesis of N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride
  • 6-cyclopropyl-2-methyl-2H-indazol-5-amine (285 mg, 1.5240 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (373 mg, 1.8288 mmol) using EDCI.HCl (438 mg, 2.2860 mmol), HOBt (309 mg, 2.2860 mmol), DIPEA (1.061 mL, 6.0962 mmol) in DMF (12 mL) to afford the crude compound which on treatment with methanolic HCl afforded the title compound (396 mg, 63.46%).
  • Step-1 Synthesis of 6-chloro-1-cyclopentyl-5-nitro-1H-indazole and 6-chloro-2-cyclopentyl-5-nitro-2H-indazole
  • 6-chloro-5-nitro-2H-indazole (1 gm, 5.063 mmol) was alkylated with cyclopentylbromide (836 mg, 5.569 mmol) and potassium carbonate (2.1 gm, 15.189 mmol) in DMF (10 mL) to get the crude product.
  • Step-2 Synthesis of 1-cyclopentyl-6-cyclopropyl-5-nitro-1H-indazole
  • 6-chloro-1-cyclopentyl-5-nitro-1H-indazole 500 mg, 1.858 mmol
  • cyclopropyl boronic acid 400 mg, 4.646 mmol
  • Pd(OAc) 2 127 mg, 0.557 mmol
  • tricyclohexyl phosphine 156 mg, 0.557 mmol
  • potassium carbonate 770 mg, 5.57 mmol
  • toluene/H 2 O 15/2 mL
  • Step-4 Synthesis of N-(1-cyclopentyl-6-cyclopropyl-1H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide
  • 1-cyclopentyl-6-cyclopropyl-1H-indazol-5-amine 100 mg, 0.413 mmol
  • 6-(1-methyl-1H-pyrazol-4-yl)picolinic acid intermediate 2
  • EDCI.HCl 117 mg, 0.619 mmol
  • HOBt 84 mg, 0.619 mmol
  • DIPEA 160 mg, 1.239 mmol
  • DMF 5 mL
  • 2-cyclopentyl-6-cyclopropyl-2H-indazol-5-amine (product of step 2 of example 6) (100 mg, 0.413 mmol) was coupled with 6-(1-methyl-1H-pyrazol-4-yl)picolinic acid (intermediate 2) (92 mg, 0.454 mmol) using EDCI.HCl (117 mg, 0.619 mmol), HOBt (84 mg, 0.619 mmol), DIPEA (160 mg, 1.239 mmol) in DMF (5 mL) to get the crude product. This was then purified by prep. HPLC to obtain the desired compound (80 mg, 51%).
  • 2-cyclopentyl-6-cyclopropyl-2H-indazol-5-amine (product of step 2 of example 6) (80 mg, 0.330 mmol) was coupled with 2-(6-methoxypyridin-3-yl)oxazole-4-carboxylic acid (intermediate 3) (73 mg, 0.330 mmol) using EDCI.HCl (95 mg, 0.4958 mmol), HOBt (47 mg, 0.3471 mmol), DIPEA (150 mg, 1.160 mmol) in DMF (5 mL) to obtain the desired compound (41 mg, 28%).
  • 2-methyl-6-(piperidin-1-yl)-2H-indazol-5-amine (product of step 6 of example 1) (80 mg, 0.3478 mmol) was coupled with 2-(3-methylpyridin-4-yl)oxazole-4-carboxylic acid (PCT publication: WO2011043371 dated Apr. 14, 2011) (96 mg, 0.4695 mmol) using EDCI.HCl (135 mg, 0.7047 mmol), HOBt (64 mg, 0.4695 mmol), DIPEA (212 mg, 1.64 mmol) in DMF (5 mL) to obtain the desired compound (130 mg, 90.2%).
  • 2-methyl-6-(piperidin-1-yl)-2H-indazol-5-amine (product of step 6 of example 1) (450 mg, 1.9538 mmol) was coupled with 6-bromopicolinic acid (474 mg, 2.344 mmol) using EDCI.HCl (562 mg, 2.9308 mmol), HOBt (396 mg, 2.9308 mmol), DIPEA (1.361 mL, 7.8155 mmol) in DMF (20 mL) to obtain the desired compound (700 mg, 86.52%).
  • 2-methyl-6-(piperidin-1-yl)-2H-indazol-5-amine (product of step 6 of example 1) (300 mg, 1.3025 mmol) was coupled with 6-chloro-5-methylpicolinic acid (269 mg, 1.5631 mmol) using EDCI.HCl (375 mg, 1.9538 mmol), HOBt (264 mg, 1.9538 mmol), DIPEA (0.907 mL, 5.2103 mmol) in DMF (15 mL) to obtain the desired compound (375 mg, 75.0%).
  • 2-methyl-6-(piperidin-1-yl)-2H-indazol-5-amine (product of step 6 of example 1) (80 mg, 0.3478 mmol) was coupled with 2-(2-methylpyridin-5-yl)oxazole-4-carboxylic acid (96 mg, 0.4695 mmol) using EDCI.HCl (135 mg, 0.7047 mmol), HOBt (64 mg, 0.4695 mmol), DIPEA (212 mg, 1.64 mmol) in DMF (5 mL) to obtain the title compound (112 mg, 77%).
  • 2-cyclopentyl-6-cyclopropyl-2H-indazol-5-amine (product of step 2 of example 6) (75 mg, 0.309 mmol) was coupled with 2-(2-methylpyridin-3-yl)oxazole-4-carboxylic acid (intermediate 4) (75 mg, 0.371 mmol) using EDCI.HCl (88 mg, 0.464 mmol), HOBt (42 mg, 0.309 mmol), DIPEA (0.3 mL, 1.236 mmol) in DMF (5 mL) to afford the crude compound which after purification by prep HPLC afforded the title compound (50 mg, 38%).
  • 2-cyclopentyl-6-cyclopropyl-2H-indazol-5-amine (product of step 2 of example 6) (75 mg, 0.309 mmol) was coupled with 2-(3-methylpyridin-4-yl)oxazole-4-carboxylic acid (75 mg, 0.371 mmol) using EDCI.HCl (88 mg, 0.464 mmol), HOBt (42 mg, 0.309 mmol), DIPEA (0.3 mL, 1.236 mmol) in DMF (4 mL) to afford the crude compound which after purification by prep HPLC afforded the title compound (50 mg, 38%).
  • 2-cyclopentyl-6-cyclopropyl-2H-indazol-5-amine (product of step 2 of example 6) (100 mg, 0.4132 mmol) was coupled with 2-(2-methylpyridin-5-yl)oxazole-4-carboxylic acid (WO2011043371) (102 mg, 0.4958 mmol) using EDCI.HCl (119 mg, 0.6198 mmol), HOBt (84 mg, 0.6198 mmol), DIPEA (0.288 L, 1.6528 mmol) in DMF (2 mL) to afford the crude compound which after purification by prep HPLC afforded the title compound (70 mg, 36.64%).
  • Step-1 Synthesis of tert-butyl (3-methyl-6-((2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)carbamoyl)-[2,3′-bipyridin]-6′-yl)carbamate
  • 6-chloro-5-methyl-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide (example 24) (100 mg, 0.2605 mmol) was coupled with tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl)carbamate (product of step 2 of example 9) (167 mg, 0.5210 mmol) using Pd(dppf)Cl 2 (10 mg, 0.0130 mmol) and sodium carbonate (69 mg, 0.6512 mmol) in DME/H 2 O (5/2 mL) at 90° C.
  • Step-2 Synthesis of 6′-amino-3-methyl-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-[2,3′-bipyridine]-6-carboxamide hydrochloride
  • tert-butyl (3-methyl-6-((2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)carbamoyl)-[2,3′-bipyridin]-6′-yl)carbamate 100 mg, 0.1846 mmol was deprotected using methanolic HCl (5 mL) and purified by prep HPLC to get the title compound (70 mg, 79.54%).
  • 6-chloro-5-methyl-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide (example 24) (100 mg, 0.2605 mmol) was coupled with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-Pyrazole (109 mg, 0.5210 mmol) using Pd(dppf)Cl 2 (10 mg, 0.0130 mmol) and sodium carbonate (69 mg, 0.6512 mmol) in DME/H 2 O (5/2 mL) at 90° C. for 12 h to obtain crude product. This was purified by silica gel column chromatography and elution with 2% methanol in DCM gave the title compound (30 mg, 24.79%).
  • Step-1 Synthesis of 1-cyclopropyl-5-nitro-6-(piperidin-1-yl)-1H-indazole
  • 5-nitro-6-(piperidin-1-yl)-1H-indazole product of step 4 of example 1 (800 mg, 3.4060 mmol) was coupled with cyclopropyl boronic acid (837 mg, 9.7446 mmol) using Cu(OAc) 2 (708 mg, 3.8978 mmol), 2,2′-bipyridine (609 mg, 3.8978 mmol) and sodium carbonate (1.032 gm, 9.7446 mmol) in dichloroethane (50 mL) at 70° C. for 2 h to get the crude compound.
  • Step-2 Synthesis of 1-cyclopropyl-6-(piperidin-1-yl)-1H-indazol-5-amine
  • Step-3 Synthesis of N-(1-cyclopropyl-6-(piperidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride
  • 2-methyl-6-(piperidin-1-yl)-2H-indazol-5-amine (product of step 6 of example 1) (70 mg, 0.304 mmol) was coupled with 2-(2-hydroxypyridin-3-yl)oxazole-4-carboxylic acid (intermediate 5) (56 mg, 0.273 mmol) using EDCI.HCl (87 mg, 0.456 mmol), HOBt (62 mg, 0.456 mmol), DIPEA (98 mg, 0.76 mmol) in DMF (3 mL) to obtain the crude product. The obtained crude was purified by using prep HPLC to obtain the desired compound (9 mg, 7%).
  • Step-1 Synthesis of tert-butyl (S)-(1-(6-((2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate
  • 6-bromo-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide (example 23) (100 mg, 0.2413 mmol) was coupled with tert-butyl (S)-pyrrolidin-3-ylcarbamate (90 mg, 0.4827 mmol) using Pd(OAc) 2 (6 mg, 0.0241 mmol), xantphos (14 mg, 0.0241 mmol) and caesium carbonate (157 mg, 0.6034 mmol) in 1,4-dioxane (5 mL) at 110° C. for 12 h to obtain crude product. (60 mg, 48.0%).
  • LCMS: m/z 520.3 (M+1) + .
  • Step-2 Synthesis of (S)-6-(3-aminopyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide 2,2,2-trifluoroacetate
  • tert-butyl (S)-(1-(6-((2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate 60 mg, 0.1154 mmol was deprotected using methanolic HCl (2 mL), purified by prep HPLC and treated with TFA to get the title compound (12 mg, 19.67%).
  • N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl) picolinamide (example 1) (500 mg, 1.14 mmol), (S)-2-methyloxirane (133 mg, 2.29 mmol), sodium carbonate (607 mg, 5.73 mmol) and DMF (10 mL) were taken and heated at 140° C. for 4 h. The reaction was quenched with ice water and extracted with ethyl acetate. The obtained crude was purified by using prep. HPLC to get the title compound (295 mg, 56.08%).
  • 6-bromo-5-nitro-1H-indazole product of step 2 of example 5
  • 6-bromo-5-nitro-1H-indazole product of step 2 of example 5
  • cyclopropyl boronic acid 710 mg, 8.2644 mmol
  • Cu(OAc) 2 901 mg, 4.9586 mmol
  • 2,2′-bipyridine 775 mg, 4.9586 mmol
  • sodium carbonate 1.314 gm, 12.3966 mmol
  • dichloroethane 20 mL
  • Step-4 Synthesis of N-(1,6-dicyclopropyl-1H-indazol-5-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide
  • 1,6-dicyclopropyl-1H-indazol-5-amine 130 mg, 0.6095 mmol
  • 2-(6-methoxypyridin-3-yl)oxazole-4-carboxylic acid 161 mg, 0.7314 mmol
  • EDCI.HCl (175 mg, 0.9142 mmol
  • HOBt 124 mg, 0.9142 mmol
  • DIPEA 0.432 mL, 2.4381 mmol
  • 1,6-dicyclopropyl-1H-indazol-5-amine (product of step 3 of example 35) (130 mg, 0.6132 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (150 mg, 0.7358 mmol) using EDCI.HCl (177 mg, 0.9198 mmol), HOBt (125 mg, 0.9198 mmol), DIPEA (0.428 mL, 2.4528 mmol) in DMF (2 mL) to get the crude product. This was then purified by prep HPLC and treated with methanolic HCl to obtain the desired compound (75 mg, 30.61%).
  • 6-bromo-1-methyl-5-nitro-1H-indazole product of step 1 of example 11
  • cyclopropyl boronic acid 335 mg, 3.90 mmol
  • Pd(OAc) 2 44 mg, 1.95 mmol
  • tricyclohexyl phosphine 55 mg, 1.95 mmol
  • potassium phosphate (1.03 gm, 4.88 mmol) in toluene/H 2 O (8/2 mL) at 110° C. for 4 h to obtain crude product.
  • 6-cyclopropyl-1-methyl-5-nitro-1H-indazole 300 mg, 1.3810 mmol was reduced using 10% Pd/C (30 mg) in methanol (10 mL) for 4 h to get the desired product (240 mg, 85.7%).
  • LCMS: 98.17%, m/z 188.1 (M+1) + .
  • 6-cyclopropyl-1-methyl-1H-indazol-5-amine (240 mg, 1.28 mmol) was coupled with 6-bromopicolinic acid (311 mg, 1.54 mmol) using EDCI.HCl (368 mg, 1.94 mmol), HOBt (181 mg, 1.34 mmol), DIPEA (496 mg, 3.85 mmol) in DMF (5 mL) to obtain the desired compound (300 mg, 56.05%).
  • Step-4 Synthesis of (S)—N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide
  • 6-bromo-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide (example 23) (20 mg, 0.483 mmol) was substituted with pyrrolidin-3-ol (9 mg, 0.0724 mmol) using sodium carbonate (15 mg, 0.1449 mmol) in DMF (2 mL) at 140° C. for 14 h to get the title compound (16 mg, 80%).
  • 6-bromo-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide (example 23) (75 mg, 0.1811 mmol) was substituted with tert-butyl (R)-pyrrolidin-3-ylcarbamate (68 mg, 0.362 mmol) using sodium carbonate (58 mg, 0.5434 mmol) in DMF (5 mL) at 140° C. for 14 h to get the crude product which was deprotected using TFA/DCM (1/3 mL) to get the title compound (35 mg, 61.87%).
  • 6-cyclopropyl-1-methyl-1H-indazol-5-amine product of step 2 of example 37
  • 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid 170 mg, 1.54 mmol
  • EDCI.HCl 199 mg, 1.0427 mmol
  • HOBt 94 mg, 0.069 mmol
  • DIPEA 358 mg, 2.78 mmol
  • DMF 3 mL
  • Step-1 Synthesis of 6-bromo-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)picolinamide
  • 6-cyclopropyl-2-methyl-2H-indazol-5-amine (product of step 2 of example 16) (270 mg, 1.44 mmol) was coupled with 6-bromopicolinic acid (290 mg, 1.44 mmol) using EDCI.HCl (414 mg, 2.16 mmol), HOBt (204 mg, 1.51 mmol), DIPEA (750 mg, 5.76 mmol) in DMF (5 mL) to obtain the desired compound (434 mg, 81%).
  • HPLC 90.39%.
  • Step-2 Synthesis of N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide
  • Step-3 Synthesis of N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)picolinamide hydrochloride
  • N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide 148 mg, 0.334 mmol
  • ether HCl 5 mL
  • methanol 5 mL
  • Step-4 Synthesis of (S)—N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)picolinamide
  • N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)picolinamide hydrochloride (100 mg, 2.5 mmol) was substituted with (S)-2-methyloxirane (30 mg, 5 mmol) using sodium carbonate (133 mg, 12.5 mmol) in DMF (5 mL) at 100° C. for 14 h to get the title compound (19 mg, 18%).
  • Step-1 Synthesis of tert-butyl (S)-(1-(6-((6-cyclopropyl-2-methyl-2H-indazol-5-yl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate
  • 6-bromo-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)picolinamide product of step 1 of example 47
  • tert-butyl (S)-pyrrolidin-3-ylcarbamate 75 mg, 0.404 mmol
  • sodium carbonate 86 mg, 0.808 mmol
  • Step-2 Synthesis of(S)-6-(3-aminopyrrolidin-1-yl)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)picolinamide
  • Step-1 Synthesis of (S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)oxazole-4-carboxamide
  • 6-cyclopropyl-1-methyl-1H-indazol-5-amine (product of step 2 of example 37) (80 mg, 0.4278 mmol) was coupled with (S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylic acid (intermediate 9) (152 mg, 0.513 mmol) using EDCI.HCl (122 mg, 0.6417 mmol), HOBt (86 mg, 0.6417 mmol), DIPEA (220 mg, 1.7112 mmol) in DMF (2 mL) to obtain the crude product.
  • Step-2 Synthesis of (S)—N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxamide
  • step 7 of example 1 6-cyclopropyl-1-methyl-1H-indazol-5-amine (product of step 2 of example 37) (80 mg, 0.4278 mmol) was coupled with (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylic acid (intermediate 7) (160 mg, 0.513 mmol) using EDCI.HCl (122 mg, 0.6417 mmol), HOBt (86 mg, 0.6417 mmol), DIPEA (220 mg, 1.711 mmol) in DMF (3 mL) to obtain the crude product.
  • step 8 of example 1 above crude product was deprotected using TFA/DCM (1/1 mL) to get the title compound (70 mg, 69.3%).
  • Step-1 Synthesis of N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxamide
  • 6-cyclopropyl-1-methyl-1H-indazol-5-amine (product of step 2 of example 37) (100 mg, 0.534 mmol) was coupled with 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxylic acid (intermediate 10) (120 mg, 0.534 mmol) using EDCI.HCl (152 mg, 0.801 mmol), HOBt (108 mg, 0.801 mmol), DIPEA (275 mg, 2.136 mmol) in DMF (5 mL) to obtain the title compound (212 mg, 91.7%).
  • LCMS: m/z 433.2 (M+1).
  • Step-2 Synthesis of N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide hydrochloride
  • N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxamide 212 mg, 0.490 mmol
  • methanolic HCl 5 mL
  • methanol 1 mL
  • Step-3 Synthesis of (S)—N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide
  • Step-1 Synthesis of tert-butyl (S)-(1-(4-((6-cyclopropyl-2-methyl-2H-indazol-5-yl)carbamoyl)oxazol-2-yl)pyrrolidin-3-yl)carbamate
  • step 7 of example 1 6-cyclopropyl-2-methyl-2H-indazol-5-amine (product of step 2 of example 16) (85 mg, 0.4545 mmol) was coupled with (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylic acid (intermediate 7) (162 mg, 0.5454 mmol) using EDCI.HCl (157 mg, 0.8181 mmol), HOBt (77 mg, 0.5726 mmol), DIPEA (282 mg, 2.185 mmol) in DMF (5 mL) to obtain the desired compound (142 mg, 67%).
  • LCMS: m/z 467.3 (M+1) + .
  • Step-2 Synthesis of (S)-2-(3-aminopyrrolidin-1-yl)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)oxazole-4-carboxamide
  • tert-butyl (S)-(1-(4-(((6-cyclopropyl-2-methyl-2H-indazol-5-yl)carbamoyl)oxazol-2-yl)pyrrolidin-3-yl)carbamate 141 mg, 0.3025 mmol was deprotected using ether HCl/methanol (5/5 mL) to get the title compound (32 mg, 29%).
  • Step-1 Synthesis of (S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)oxazole-4-carboxamide
  • Step-2 Synthesis of (S)—N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxamide
  • Step-1 Synthesis of N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide
  • 6-bromo-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide product of step 1 of example 12
  • 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 144 mg, 0.5204 mmol
  • Pd(dppf)Cl 2 31 mg, 0.0433 mmol
  • sodium carbonate 137 mg, 1.3012 mmol
  • Step-2 Synthesis of N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)picolinamide hydrochloride
  • N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide 120 mg was deprotected using methanolic HCl (5 mL) in methanol (10 mL) to get the title compound (100 mg, 98%).
  • LCMS: m/z 403.2 (M+1) + .
  • Step-3 Synthesis of (S)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide
  • N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)picolinamide hydrochloride (100 mg, 0.2487 mmol) was reacted with (S)-2-methyloxirane (28 mg, 0.497 mmol) using sodium carbonate (131 mg, 1.243 mmol) in DMF (3 mL) at 100° C. for 14 h to get the crude product.
  • the obtained crude was purified by 60-120 silica gel column chromatography using methanol in DCM as eluent to obtain the crude product. This was purified by prep HPLC to get the title compound (60 mg, 53%).
  • Step-2 Synthesis of 4-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-fluoro-5-nitrobenzaldehyde
  • Step-4 Synthesis of 6-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-1-methyl-5-nitro-1H-indazole and 6-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-methyl-5-nitro-2H-indazole
  • Step-5 Synthesis of 6-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-methyl-2H-indazol-5-amine
  • Step-6 Synthesis of N-(6-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • Step-7 Synthesis of N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • Step-3 Synthesis of 6-(azetidin-1-yl)-1-methyl-5-nitro-1H-indazole (Isomer A) and 6-(azetidin-1-yl)-2-methyl-5-nitro-2H-indazole (Isomer B)
  • 6-(azetidin-1-yl)-5-nitro-1H-indazole (1.2 gm, 5.17 mmol) was methylated using sodium hydride (260 mg, 10.8 mmol) and methyl iodide (3.01 gm, 29.2 mmol) in THF (15 mL) at RT for 0.5 h to get the crude product.
  • This was purified by silica gel column chromatography and elution with 50% ethyl acetate in hexane gave the title compound (isomer A 600 mg and isomer B 300 mg, 70%).
  • LCMS: m/z 233.0 (M+1) + .
  • Step-5 Synthesis of N-(6-(azetidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • 6-(azetidin-1-yl)-1-methyl-1H-indazol-5-amine 250 mg, 0.23 mmol
  • 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid 302 mg, 0.248 mmol
  • HATU 705 mg, 1.85 mmol
  • DIPEA 638 mg, 4.955 mmol
  • DMF 8 mL
  • step 2 of example 16 6-(azetidin-1-yl)-2-methyl-5-nitro-2H-indazole (300 mg, 1.74 mmol) (product of step 3 of example 59) was reduced with zinc dust (1.13 gm, 17.4 mmol) and ammonium chloride (941 mg, 17.4 mmol) in THF/water (10/2 mL) to get the desired crude product (250 mg).
  • LCMS: m/z 203.2 (M+1) + .
  • Step-2 Synthesis of N-(6-(azetidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • 6-(azetidin-1-yl)-2-methyl-2H-indazol-5-amine 250 mg, 1.23 mmol
  • 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid 302 mg, 1.48 mmol
  • HATU 705 mg, 1.85 mmol
  • DIPEA 638 mg, 4.95 mmol
  • Step-2 Synthesis of 4-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2-fluoro-5-nitrobenzaldehyde
  • Step-4 Synthesis of 6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-5-nitro-1H-indazole
  • Step-5 Synthesis of 6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-1-methyl-5-nitro-1H-indazole compound and 6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2-methyl-5-nitro-2H-indazole
  • 6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-5-nitro-1H-indazole (1.8 gm, 5.1652 mmol) was methylated using sodium hydride (416 mg, 10.4046 mmol) and methyl iodide (0.65 mL), 10.4046 mmol) in THF (20 mL) at 0° C. for 1 h to get the crude product.
  • Step-6 Synthesis of 6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2-methyl-2H-indazol-5-amine
  • Step-7 Synthesis of N-(6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • Step-8 Synthesis of N-(6-(3-hydroxyazetidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • N-(6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide 100 mg, 0.1927 mmol
  • Step-3 Synthesis of 1-methyl-5-nitro-6-(pyrrolidin-1-yl)-1H-indazole and 2-methyl-5-nitro-6-(pyrrolidin-1-yl)-2H-indazole
  • 5-nitro-6-(pyrrolidin-1-yl)-1H-indazole (2.15 gm, 9.4298 mmol) was methylated using sodium hydride (754 mg, 18.8596 mmol) and methyl iodide (1.179 mL, 18.8596 mmol) in THF (80 mL) at RT for 3 h to get the crude product.
  • Step-5 Synthesis of N-(1-methyl-6-(pyrrolidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • 1-methyl-6-(pyrrolidin-1-yl)-1H-indazol-5-amine 150 mg, 0.6935 mmol
  • 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid 170 mg, 0.8322 mmol
  • HATU 343 mg, 0.9015 mmol
  • DIPEA 0.483 mL, 2.7740 mmol
  • DMF 3 mL
  • Step-2 Synthesis of N-(2-methyl-6-(pyrrolidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • 2-methyl-6-(pyrrolidin-1-yl)-1H-indazol-5-amine (170 mg, 0.7859 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (193 mg, 0.9431 mmol) using HATU (388 mg, 1.0217 mmol), DIPEA (0.548 mL, 3.1439 mmol) in DMF (3 mL) to get the desired compound (70 mg, 22.22%).
  • Step-1 Synthesis of 6-fluoro-1-methyl-5-nitro-1H-indazole (Isomer A) and 6-fluoro-2-methyl-5-nitro-2H-indazole (Isomer B)
  • 6-fluoro-5-nitro-1H-indazole product of step 3 of example 1
  • THF 20 mL
  • isomer B 800 mg and isomer A 1.1 gm, 90% was methylated using sodium hydride (696 mg, 29.0 mmol and methyl iodide (8.04 gm, 56.6 mmol) in THF (20 mL) at RT for 0.5 h to get the crude product.
  • Step-3 Synthesis of (S)-6-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-methyl-5-nitro-2H-indazole
  • Step-4 Synthesis of (S)-6-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-methyl-2H-indazol-5-amine
  • Step-5 Synthesis of (S)—N-(6-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • Step-6 Synthesis of (S)—N-(6-(3-hydroxypyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • step 1 of example 58 6-fluoro-2-methyl-5-nitro-2H-indazole (product of step 1 of example 64) (250 mg, 1.28 mmol) was substituted with (R)-pyrrolidin-3-ol (133 mg, 1.52 mmol) using potassium carbonate (530 mg, 0.384 mmol) in DMF (10 mL) at 100° C. for 12 h to get the crude compound.
  • the obtained crude was purified by 60-120 silica gel column chromatography and compound eluted using 50% ethyl acetate in hexane to give title compound (200 mg, 60.6%).
  • LCMS: m/z 263.1 (M+1) + .
  • Step-2 Synthesis of (R)-6-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-methyl-5-nitro-2H-indazole
  • Step-3 Synthesis of (R)-6-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-methyl-2H-indazol-5-amine
  • Step-4 Synthesis of (R)—N-(6-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • Step-5 Synthesis of (R)—N-(6-(3-hydroxypyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • Step-1 Synthesis of N-(6-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide
  • step 7 of example 1 6-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-methyl-2H-indazol-5-amine (product of step 5 of example 58) (110 mg, 0.3055 mmol) was coupled with 5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (intermediate 12) (74 mg, 0.366 mmol) using HATU (174 mg, 0.458 mmol) and DIPEA (0.2 mL, 1.222 mmol) in DMF (5 mL) to afford the title compound (150 mg, 94%).
  • LCMS: m/z 546.2 (M+1) + .
  • Step-2 Synthesis of N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide
  • N-(6-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide (100 mg, 0.1927 mmol) was deprotected using 0.1M TBAF in THF/THF (1/2 mL) at RT for 2 h to get the title compound (130 mg, 90%).
  • Step-2 Synthesis of 4-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-fluoro-5-nitrobenzaldehyde
  • Step-4 Synthesis of 6-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-1-methyl-5-nitro-1H-indazole and 6-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-methyl-5-nitro-2H-indazole
  • 6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-5-nitro-1H-indazole (1.5 gm, 5.84 mmol) was methylated using sodium hydride (193 mg, 8.07 mmol) and methyl iodide (2.23 mL), 15.7 mmol) in THF (20 mL) at RT for 0.5 h to get the crude product.
  • Step-5 Synthesis of 6-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-methyl-2H-indazol-5-amine
  • Step-6 Synthesis of N-(6-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • Step-7 Synthesis of N-(6-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • N-(6-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide 130 mg, mmol
  • Step-2 Synthesis of (R)-4-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-fluoro-5-nitrobenzaldehyde
  • Step-3 Synthesis of (R)-6-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-5-nitro-1H-indazole
  • Step-4 Synthesis of (R)-6-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-1-methyl-5-nitro-1H-indazole and (R)-6-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-methyl-5-nitro-2H-indazole
  • Step-5 Synthesis of (R)-6-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-methyl-2H-indazol-5-amine
  • Step-6 Synthesis of (R)—N-(6-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide
  • Step-7 Synthesis of (R)—N-(6-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide
  • Step-1 Synthesis of N-(6-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide
  • Step-2 Synthesis of N-(6-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide
  • N-(6-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide 130 mg, 0.296 mmol
  • Step-3 Synthesis of 6-(azepan-1-yl)-1-methyl-5-nitro-1H-indazole 6-(azepan-1-yl)-2-methyl-5-nitro-2H-indazole
  • 6-(azepan-1-yl)-5-nitro-1H-indazole (1 gm, 3.89 mmol) was methylated using sodium hydride (372 mg, 7.78 mmol) and methyl iodide (0.5 mL, 7.7 mmol) in THF (20 mL) at RT for 0.5 h to get the crude product.
  • Step-5 Synthesis of N-(6-(azepan-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • 6-(azepan-1-yl)-2-methyl-2H-indazol-5-amine 120 mg, 0.4918 mmol
  • 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid 120 mg, 0.590 mmol
  • HATU 280 mg, 0.737 mmol
  • DIPEA 0.4 mL, 1.9672 mmol
  • DMF 5 mL
  • Step-2 Synthesis of N-(6-(azepan-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
  • 6-(azepan-1-yl)-1-methyl-2H-indazol-5-amine 120 mg, 0.4918 mmol
  • 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid 120 mg, 0.590 mmol
  • HATU 280 mg, 0.737 mmol
  • DIPEA 0.4 mL, 1.9672 mmol
  • DMF 5 mL
  • 6-fluoro-3-methyl-1H-indazole (1.6 gm, 10.6 mmol) was nitrated using KNO 3 (1.292 gm, 12.7 mmol) and sulphuric acid (20 mL) at RT for 2 h to get the title impure compound (650 mg) which was used as such for next step.
  • Step-4 Synthesis of 1,3-dimethyl-5-nitro-6-(piperidin-1-yl)-1H-indazole and 2,3-dimethyl-5-nitro-6-(piperidin-1-yl)-2H-indazole
  • 3-methyl-5-nitro-6-(piperidin-1-yl)-1H-indazole 650 mg, 2.5 mmol was methylated using sodium hydride (200 mg, 5 mmol) and methyl iodide (0.313 mL, 5 mmol) in THF (20 mL) at RT for 2 h to get the crude product.
  • Step-6 Synthesis of N-(2,3-dimethyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Cardiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pulmonology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Epidemiology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Obesity (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Neurology (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Oncology (AREA)
  • Dermatology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US15/110,309 2014-01-10 2015-01-07 Indazole compounds as IRAK4 inhibitors Expired - Fee Related US10160753B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
IN146CH2014 2014-01-10
IN146/CHE/2014 2014-01-10
IN3018CH2014 2014-06-20
IN3018/CHE/2014 2014-06-20
PCT/IB2015/050119 WO2015104662A1 (en) 2014-01-10 2015-01-07 Indazole compounds as irak4 inhibitors

Publications (2)

Publication Number Publication Date
US20160326151A1 US20160326151A1 (en) 2016-11-10
US10160753B2 true US10160753B2 (en) 2018-12-25

Family

ID=52462359

Family Applications (1)

Application Number Title Priority Date Filing Date
US15/110,309 Expired - Fee Related US10160753B2 (en) 2014-01-10 2015-01-07 Indazole compounds as IRAK4 inhibitors

Country Status (16)

Country Link
US (1) US10160753B2 (pt)
EP (1) EP3092226B1 (pt)
JP (1) JP2017505337A (pt)
KR (1) KR20160115933A (pt)
CN (1) CN106458982A (pt)
AU (1) AU2015205348A1 (pt)
BR (1) BR112016015983A2 (pt)
CA (1) CA2935880A1 (pt)
CU (1) CU20160109A7 (pt)
EA (1) EA201691401A1 (pt)
HK (1) HK1231480A1 (pt)
IL (1) IL246555A0 (pt)
MX (1) MX2016009011A (pt)
PH (1) PH12016501338A1 (pt)
SG (1) SG11201605408RA (pt)
WO (1) WO2015104662A1 (pt)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10758518B2 (en) 2017-10-31 2020-09-01 Curis, Inc. Compounds and compositions for treating hematological disorders
US10995100B2 (en) 2014-01-13 2021-05-04 Aurigene Discovery Technologies Limited Bicyclic heterocyclyl derivatives as IRAK4 inhibitors
WO2021198980A1 (en) 2020-04-04 2021-10-07 Pfizer Inc. Methods of treating coronavirus disease 2019
US11254667B2 (en) 2016-08-17 2022-02-22 Children's Hospital Medical Center Substituted imidazo[1,2-A]pyridines as IRAK 1/4 and flt3 inhibitors
US11419875B2 (en) 2017-03-31 2022-08-23 Aurigene Discovery Technologies Limited Compounds and compositions for treating hematological disorders
US11542261B2 (en) 2016-08-17 2023-01-03 Children's Hospital Medical Center Substituted Imidazo[1,2-a]-pyridines as IRAK 1/4 and FLT3 inhibitors
US11897863B2 (en) 2018-08-17 2024-02-13 Zhejiang Hisun Pharmaceutical Co., Ltd. Indazole amine derivative, preparation method therefor and medical use thereof

Families Citing this family (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB201311891D0 (en) 2013-07-03 2013-08-14 Glaxosmithkline Ip Dev Ltd Novel compound
GB201311888D0 (en) 2013-07-03 2013-08-14 Glaxosmithkline Ip Dev Ltd Novel compounds
KR20160115933A (ko) 2014-01-10 2016-10-06 오리진 디스커버리 테크놀로지스 리미티드 Irak4 억제제로서의 인다졸 화합물
KR20170016500A (ko) * 2014-06-20 2017-02-13 오리진 디스커버리 테크놀로지스 리미티드 Irak4 저해제로서의 치환된 인다졸 화합물
JO3705B1 (ar) 2014-11-26 2021-01-31 Bayer Pharma AG إندازولات مستبدلة جديدة، عمليات لتحضيرها، مستحضرات دوائية تحتوي عليها واستخدامها في إنتاج أدوية
WO2016096709A1 (en) 2014-12-16 2016-06-23 Eudendron S.R.L. Heterocyclic derivatives modulating activity of certain protein kinases
EP3195865A1 (de) 2016-01-25 2017-07-26 Bayer Pharma Aktiengesellschaft Kombinationen von irak4 inhibitoren und btk inhibitoren
US20180289685A1 (en) 2015-04-30 2018-10-11 Bayer Pharma Aktiengesellschaft Combinations of inhibitors of irak4 with inhibitors of btk
MX2018000512A (es) * 2015-07-15 2018-04-13 Aurigene Discovery Tech Ltd Compuestos de indazaol y azaindazol como inhibidores de la cinasa 4 asociada al receptor de interlucina 1 (irak-4).
CA2993661A1 (en) * 2015-08-04 2017-02-09 Rigel Pharmaceuticals, Inc. Benzazole compounds and methods for making and using the compounds
DK3347353T3 (da) * 2015-09-11 2019-10-21 Boehringer Ingelheim Int Pyrazolyl-substituerede heteroaryler og deres anvendelse som lægemidler
WO2017108744A1 (de) * 2015-12-22 2017-06-29 Bayer Pharma Aktiengesellschaft Neue substituierte indazole, verfahren zu ihrer herstellung, pharmazeutische präparate die diese enthalten, sowie deren verwendung zur herstellung von arzneimitteln
WO2017148902A1 (de) 2016-03-03 2017-09-08 Bayer Pharma Aktiengesellschaft Neue 2-substituierte indazole, verfahren zu ihrer herstellung, pharmazeutische präparate die diese enthalten, sowie deren verwendung zur herstellung von arzneimitteln
CA3022332A1 (en) 2016-04-29 2017-11-02 Bayer Pharma Aktiengesellschaft Polymorphic form of n-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2h-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide
MA44758A (fr) * 2016-04-29 2019-03-06 Bayer Pharma AG Formes cristallines de n-[2-(3-hydroxy-3-méthylbutyl)-6-(2-hydroxypropan-2-yl)-2h-indazol-5-yl]-6-(trifluorométhyl)pyridine-2-carboxamide
WO2017207385A1 (de) 2016-05-31 2017-12-07 Bayer Pharma Aktiengesellschaft Substituierte 3-methylindazole, verfahren zu ihrer herstellung, pharmazeutische präparate, die diese enthalten, sowie deren verwendung zur herstellung von arzneimitteln
SG11201809470RA (en) * 2016-06-01 2018-11-29 Bayer Animal Health Gmbh Substituted indazoles useful for treatment and prevention of allergic and/or inflammatory diseases in animals
JP7099966B2 (ja) * 2016-06-01 2022-07-12 バイエル・ファルマ・アクティエンゲゼルシャフト 自己免疫疾患を治療および予防するための２－置換インダゾールの使用
WO2018049214A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyridine derivatives as hpk1 modulators and uses thereof for the treatment of cancer
CN115819417A (zh) 2016-09-09 2023-03-21 因赛特公司 作为hpk1调节剂的吡唑并吡啶衍生物及其用于治疗癌症的用途
WO2018049191A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyridone derivatives as hpk1 modulators and uses thereof for the treatment of cancer
US20180072741A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US20180228786A1 (en) 2017-02-15 2018-08-16 Incyte Corporation Pyrazolopyridine compounds and uses thereof
JOP20180011A1 (ar) 2017-02-16 2019-01-30 Gilead Sciences Inc مشتقات بيرولو [1، 2-b]بيريدازين
US10722495B2 (en) 2017-09-08 2020-07-28 Incyte Corporation Cyanoindazole compounds and uses thereof
EP3684366A4 (en) 2017-09-22 2021-09-08 Kymera Therapeutics, Inc. CRBN LIGANDS AND USES OF THE LATEST
IL307995A (en) 2017-09-22 2023-12-01 Kymera Therapeutics Inc Protein compounds and their uses
US11161854B2 (en) 2017-10-11 2021-11-02 Merck Sharp & Dohme Corp. Indazolyl-spiro[2.2]pentane-carbonitrile derivatives as LRRK2 inhibitors, pharmaceutical compositions, and uses thereof
US11174248B2 (en) 2017-10-11 2021-11-16 Merck Sharp & Dohme Corp. Indazolyl-spiro[2.3]hexane-carbonitrile derivatives as LRRK2 inhibitors, pharmaceutical compositions, and uses thereof
US11065231B2 (en) 2017-11-17 2021-07-20 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of interleukin-1 receptor- associated kinase 4 polypeptides
WO2019111218A1 (en) 2017-12-08 2019-06-13 Cadila Healthcare Limited Novel heterocyclic compounds as irak4 inhibitors
IL304055A (en) 2017-12-26 2023-08-01 Kymera Therapeutics Inc IRAK joints and used in them
WO2019140380A1 (en) 2018-01-12 2019-07-18 Kymera Therapeutics, Inc. Protein degraders and uses thereof
WO2019140387A1 (en) 2018-01-12 2019-07-18 Kymera Therapeutics, Inc. Crbn ligands and uses thereof
WO2019160915A1 (en) 2018-02-14 2019-08-22 Dana-Farber Cancer Institute, Inc. Irak degraders and uses thereof
PL3755703T3 (pl) 2018-02-20 2022-11-07 Incyte Corporation Pochodne n-(fenylo)-2-(fenylo)pirymidyno-4-karboksyamidu i związki pokrewne jako inhibitory hpk1 do leczenia nowotworu
US10745388B2 (en) 2018-02-20 2020-08-18 Incyte Corporation Indazole compounds and uses thereof
WO2019164847A1 (en) 2018-02-20 2019-08-29 Incyte Corporation Indazole compounds and uses thereof
US11299473B2 (en) 2018-04-13 2022-04-12 Incyte Corporation Benzimidazole and indole compounds and uses thereof
WO2020010177A1 (en) 2018-07-06 2020-01-09 Kymera Therapeutics, Inc. Tricyclic crbn ligands and uses thereof
TWI721483B (zh) 2018-07-13 2021-03-11 美商基利科學股份有限公司 吡咯并[1,2-b]嗒𠯤衍生物
US10899755B2 (en) 2018-08-08 2021-01-26 Incyte Corporation Benzothiazole compounds and uses thereof
EP3856348B1 (en) 2018-09-25 2024-01-03 Incyte Corporation Pyrazolo[4,3-d]pyrimidine compounds as alk2 and/or fgfr modulators
JP2022516401A (ja) 2018-11-30 2022-02-28 カイメラ セラピューティクス， インコーポレイテッド Ｉｒａｋ分解剤およびそれらの使用
WO2020135513A1 (zh) * 2018-12-25 2020-07-02 上海美悦生物科技发展有限公司 一种作为irak抑制剂的化合物
GB201904375D0 (en) * 2019-03-29 2019-05-15 Galapagos Nv Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders
WO2020259626A1 (zh) * 2019-06-26 2020-12-30 南京明德新药研发有限公司 作为irak4抑制剂的咪唑并吡啶类化合物
JP7340680B2 (ja) * 2019-07-10 2023-09-07 メッドシャイン ディスカバリー インコーポレイテッド Ｉｒａｋ４及びｂｔｋマルチターゲット阻害剤としてのオキサゾール化合物
AU2020326703A1 (en) 2019-08-06 2022-02-17 Incyte Corporation Solid forms of an HPK1 inhibitor
CN112480101B (zh) * 2019-09-12 2022-11-25 中国科学院上海药物研究所 一类irak4激酶抑制剂及其制备和应用
CN114466844A (zh) 2019-10-02 2022-05-10 康佳诺医疗科技发展有限公司 N-(1h-咪唑-2-基)苯甲酰胺化合物及包含其作为活性成分的药物组合物
EP4076524A4 (en) 2019-12-17 2023-11-29 Kymera Therapeutics, Inc. IRAQ DEGRADERS AND USES THEREOF
MX2022007576A (es) 2019-12-17 2022-09-23 Kymera Therapeutics Inc Degradadores de cinasas asociadas al receptor de interleucina-1 (irak) y usos de los mismos.
TW202210483A (zh) 2020-06-03 2022-03-16 美商凱麥拉醫療公司 Irak降解劑之結晶型
US11866405B2 (en) 2020-12-10 2024-01-09 Astrazeneca Ab Substituted indazoles as IRAK4 inhibitors
EP4269409A1 (en) * 2020-12-25 2023-11-01 Medshine Discovery Inc. Amide oxazole compound
WO2023088435A1 (zh) * 2021-11-19 2023-05-25 成都奥睿药业有限公司 三取代吡啶衍生物的制备及作为芳香烃受体调节物的应用
WO2023116866A1 (zh) * 2021-12-23 2023-06-29 杭州多域生物技术有限公司 一种五元并六元化合物、制备方法、药物组合物和应用
CN115181066B (zh) * 2022-06-14 2023-07-14 浙江宏元药业股份有限公司 一种6-氯-2-甲基-2h-吲唑-5-胺的合成方法

Citations (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004098518A2 (en) 2003-05-01 2004-11-18 Bristol-Myers Squibb Company Pyrazole-amide compounds useful as kinase inhibitors
WO2004108133A2 (en) 2003-06-05 2004-12-16 Vertex Pharmaceuticals Incorporated Modulators of vr1 receptor
GB2406856A (en) 2003-10-07 2005-04-13 Renovis Inc Novel amide compounds as ion channel ligands and uses thereof
EP1627869A1 (en) 2003-05-20 2006-02-22 Ajinomoto Co., Inc. Amide derivative
WO2006053227A2 (en) 2004-11-10 2006-05-18 Synta Pharmaceuticals Corp. Il-12 modulatory compounds
US20060160861A1 (en) * 2004-11-03 2006-07-20 Rolf Bohlmann Novel nicotinamide pyridinureas as vascular endothelial growth factor (VEGF) receptor kinase inhibitors
WO2007095124A2 (en) 2006-02-10 2007-08-23 Transtech Pharma, Inc. Benzazole derivatives, compositions, and methods of use as aurora kinase inhibitors
WO2007117465A2 (en) 2006-03-31 2007-10-18 Abbott Laboratories Indazole compounds
WO2008030579A2 (en) 2006-09-07 2008-03-13 Biogen Idec Ma Inc. Irak modulators for treating an inflammatory condition, cell proliferative disorder, immune disorder
WO2008030584A2 (en) 2006-09-07 2008-03-13 Biogen Idec Ma Inc. Indazole derivatives as modulators of interleukin- 1 receptor-associated kinase
WO2008073825A1 (en) 2006-12-08 2008-06-19 Exelixis, Inc. Lxr and fxr modulators
WO2009012312A1 (en) 2007-07-16 2009-01-22 Abbott Laboratories Indazoles, benzisoxazoles and benzisothiazoles as inhibitors of protein kinases
WO2009019167A1 (en) 2007-08-08 2009-02-12 Merck Serono S.A. 6-amino-pyrimidine-4-carboxamide derivatives and related compounds which bind to the sphingosine 1-phosphate (s1p) receptor for the treatment of multiple sclerosis
US20090069288A1 (en) * 2007-07-16 2009-03-12 Breinlinger Eric C Novel therapeutic compounds
WO2010071819A1 (en) 2008-12-19 2010-06-24 Schering Corporation Bicyclic heterocyclic derivatives and methods of use thereof
US20110224137A1 (en) * 2008-11-19 2011-09-15 Ting Pauline C Inhibitors of diacylglycerol acyltransferase
WO2011137219A1 (en) 2010-04-30 2011-11-03 Schering Corporation Inhibitors of phosphoinositide dependent kinase 1 (pdk1)
US20120015962A1 (en) 2010-07-13 2012-01-19 Nidhi Arora PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS
WO2012084704A1 (en) 2010-12-20 2012-06-28 Merck Serono S.A. Indazolyl triazole derivatives as irak inhibitors
WO2013042137A1 (en) 2011-09-19 2013-03-28 Aurigene Discovery Technologies Limited Bicyclic heterocycles as irak4 inhibitors
WO2013068458A1 (en) 2011-11-10 2013-05-16 Ucb Pharma S.A. Therapeutically active thiazolo-pyrimidine derivatives
WO2014003483A1 (en) 2012-06-29 2014-01-03 Hanmi Pharm. Co., Ltd. Fused pyrimidine derivatives having inhibitory activity on fms kinases
WO2015091426A1 (de) 2013-12-19 2015-06-25 Bayer Pharma Aktiengesellschaft Neue indazolcarboxamide, verfahren zu ihrer herstellung, pharmazeutische präparate die diese enthalten, sowie deren verwendung zur herstellung von arzneimitteln
WO2015104662A1 (en) 2014-01-10 2015-07-16 Aurigene Discovery Technologies Limited Indazole compounds as irak4 inhibitors
WO2017023941A1 (en) 2015-08-04 2017-02-09 Rigel Pharmaceuticals, Inc. Benzazole compounds and methods for making and using the compounds
US9732095B2 (en) 2014-01-13 2017-08-15 Aurigene Discovery Technologies Limited Bicyclic heterocyclyl derivatives as IRAK4 inhibitors
US9855273B2 (en) 2013-05-22 2018-01-02 Children's Hospital Medical Center Combination therapy for MDS

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1655297A1 (en) * 2004-11-03 2006-05-10 Schering Aktiengesellschaft Nicotinamide pyridinureas as vascular endothelial growth factor (VEGF) receptor kinase inhibitors
JP2012254939A (ja) 2009-10-07 2012-12-27 Astellas Pharma Inc オキサゾール化合物
JP2011246389A (ja) * 2010-05-26 2011-12-08 Oncotherapy Science Ltd Ｔｔｋ阻害作用を有する縮環ピラゾール誘導体
JO3705B1 (ar) 2014-11-26 2021-01-31 Bayer Pharma AG إندازولات مستبدلة جديدة، عمليات لتحضيرها، مستحضرات دوائية تحتوي عليها واستخدامها في إنتاج أدوية

Patent Citations (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004098518A2 (en) 2003-05-01 2004-11-18 Bristol-Myers Squibb Company Pyrazole-amide compounds useful as kinase inhibitors
EP1627869A1 (en) 2003-05-20 2006-02-22 Ajinomoto Co., Inc. Amide derivative
WO2004108133A2 (en) 2003-06-05 2004-12-16 Vertex Pharmaceuticals Incorporated Modulators of vr1 receptor
US7338950B2 (en) 2003-10-07 2008-03-04 Renovis, Inc. Amide compounds as ion channel ligands and uses thereof
GB2406856A (en) 2003-10-07 2005-04-13 Renovis Inc Novel amide compounds as ion channel ligands and uses thereof
US20060160861A1 (en) * 2004-11-03 2006-07-20 Rolf Bohlmann Novel nicotinamide pyridinureas as vascular endothelial growth factor (VEGF) receptor kinase inhibitors
WO2006053227A2 (en) 2004-11-10 2006-05-18 Synta Pharmaceuticals Corp. Il-12 modulatory compounds
WO2007095124A2 (en) 2006-02-10 2007-08-23 Transtech Pharma, Inc. Benzazole derivatives, compositions, and methods of use as aurora kinase inhibitors
WO2007117465A2 (en) 2006-03-31 2007-10-18 Abbott Laboratories Indazole compounds
US20120053345A1 (en) 2006-03-31 2012-03-01 Abbott Laboratories Indazole Compounds
WO2008030579A2 (en) 2006-09-07 2008-03-13 Biogen Idec Ma Inc. Irak modulators for treating an inflammatory condition, cell proliferative disorder, immune disorder
WO2008030584A2 (en) 2006-09-07 2008-03-13 Biogen Idec Ma Inc. Indazole derivatives as modulators of interleukin- 1 receptor-associated kinase
WO2008073825A1 (en) 2006-12-08 2008-06-19 Exelixis, Inc. Lxr and fxr modulators
US20090069288A1 (en) * 2007-07-16 2009-03-12 Breinlinger Eric C Novel therapeutic compounds
WO2009012312A1 (en) 2007-07-16 2009-01-22 Abbott Laboratories Indazoles, benzisoxazoles and benzisothiazoles as inhibitors of protein kinases
WO2009019167A1 (en) 2007-08-08 2009-02-12 Merck Serono S.A. 6-amino-pyrimidine-4-carboxamide derivatives and related compounds which bind to the sphingosine 1-phosphate (s1p) receptor for the treatment of multiple sclerosis
US20100210619A1 (en) * 2007-08-08 2010-08-19 Merck Serono Sa 6-Amino-Pyrimidine-4-Carboxamide Derivatives and Related Compounds Which Bind to the Sphingosine 1-Phosphate (S1P) Receptor for the Treatment of Multiple Sclerosis
US20110224137A1 (en) * 2008-11-19 2011-09-15 Ting Pauline C Inhibitors of diacylglycerol acyltransferase
WO2010071819A1 (en) 2008-12-19 2010-06-24 Schering Corporation Bicyclic heterocyclic derivatives and methods of use thereof
WO2011137219A1 (en) 2010-04-30 2011-11-03 Schering Corporation Inhibitors of phosphoinositide dependent kinase 1 (pdk1)
US20120015962A1 (en) 2010-07-13 2012-01-19 Nidhi Arora PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS
WO2012084704A1 (en) 2010-12-20 2012-06-28 Merck Serono S.A. Indazolyl triazole derivatives as irak inhibitors
WO2013042137A1 (en) 2011-09-19 2013-03-28 Aurigene Discovery Technologies Limited Bicyclic heterocycles as irak4 inhibitors
WO2013068458A1 (en) 2011-11-10 2013-05-16 Ucb Pharma S.A. Therapeutically active thiazolo-pyrimidine derivatives
WO2014003483A1 (en) 2012-06-29 2014-01-03 Hanmi Pharm. Co., Ltd. Fused pyrimidine derivatives having inhibitory activity on fms kinases
US9855273B2 (en) 2013-05-22 2018-01-02 Children's Hospital Medical Center Combination therapy for MDS
WO2015091426A1 (de) 2013-12-19 2015-06-25 Bayer Pharma Aktiengesellschaft Neue indazolcarboxamide, verfahren zu ihrer herstellung, pharmazeutische präparate die diese enthalten, sowie deren verwendung zur herstellung von arzneimitteln
WO2015104662A1 (en) 2014-01-10 2015-07-16 Aurigene Discovery Technologies Limited Indazole compounds as irak4 inhibitors
US9732095B2 (en) 2014-01-13 2017-08-15 Aurigene Discovery Technologies Limited Bicyclic heterocyclyl derivatives as IRAK4 inhibitors
WO2017023941A1 (en) 2015-08-04 2017-02-09 Rigel Pharmaceuticals, Inc. Benzazole compounds and methods for making and using the compounds

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
Alder, C. M. et al., "Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy", Med. Chem. Lett., 4:948-952 (American Chemical Society, 2013).
Ex parte Cao, Decision rendered by the Board of Patent Appeals and Interferences in U.S. Appl. No. 10/696,862 on Sep. 21, 2011 (Year: 2011). *
Extended European Search Report issued by the European Patent Office in corresponding Application No. PCT/IB2015054620 dated Jan. 16, 2018.
Extended European Search Report issued by the European Patent Office in corresponding International Application No. PCT/IB2015/050217, dated May 2, 2017.
International Search Report and Written Opinion for International Application No. PCT/IB2016/054203 dated Sep. 23, 2016.
International Search Report from parent PCT application PCT/IB2015/050217 dated Apr. 29, 2015.
International Search Report from parent PCT application PCT/IB2015/054620 dated Oct. 19, 2015.
International Search Report from published parent PCT application PCT/IB2015/050119 dated Mar. 19, 2015.

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10995100B2 (en) 2014-01-13 2021-05-04 Aurigene Discovery Technologies Limited Bicyclic heterocyclyl derivatives as IRAK4 inhibitors
US11691987B2 (en) 2014-01-13 2023-07-04 Aurigene Discovery Technologies Limited Bicyclic heterocyclyl derivatives as IRAK4 inhibitors
US11981685B2 (en) 2014-01-13 2024-05-14 Aurigene Oncology Limited Bicyclic heterocyclyl derivatives as IRAK4 inhibitors
US11254667B2 (en) 2016-08-17 2022-02-22 Children's Hospital Medical Center Substituted imidazo[1,2-A]pyridines as IRAK 1/4 and flt3 inhibitors
US11542261B2 (en) 2016-08-17 2023-01-03 Children's Hospital Medical Center Substituted Imidazo[1,2-a]-pyridines as IRAK 1/4 and FLT3 inhibitors
US11419875B2 (en) 2017-03-31 2022-08-23 Aurigene Discovery Technologies Limited Compounds and compositions for treating hematological disorders
US10758518B2 (en) 2017-10-31 2020-09-01 Curis, Inc. Compounds and compositions for treating hematological disorders
US11897863B2 (en) 2018-08-17 2024-02-13 Zhejiang Hisun Pharmaceutical Co., Ltd. Indazole amine derivative, preparation method therefor and medical use thereof
WO2021198980A1 (en) 2020-04-04 2021-10-07 Pfizer Inc. Methods of treating coronavirus disease 2019

Also Published As

Publication number Publication date
CA2935880A1 (en) 2015-07-16
US20160326151A1 (en) 2016-11-10
JP2017505337A (ja) 2017-02-16
KR20160115933A (ko) 2016-10-06
MX2016009011A (es) 2017-01-23
HK1231480A1 (zh) 2017-12-22
EP3092226A1 (en) 2016-11-16
AU2015205348A1 (en) 2016-07-28
BR112016015983A2 (pt) 2017-08-08
IL246555A0 (en) 2016-08-31
PH12016501338A1 (en) 2016-08-15
SG11201605408RA (en) 2016-07-28
EA201691401A1 (ru) 2016-11-30
WO2015104662A1 (en) 2015-07-16
EP3092226B1 (en) 2019-03-13
CN106458982A (zh) 2017-02-22
CU20160109A7 (es) 2017-02-02

Similar Documents

Publication Publication Date Title
US11981685B2 (en) Bicyclic heterocyclyl derivatives as IRAK4 inhibitors
US10160753B2 (en) Indazole compounds as IRAK4 inhibitors

Legal Events

Date Code Title Description
AS Assignment

Owner name: AURIGENE DISCOVERY TECHNOLOGIES LIMITED, INDIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GUMMADI, VENKATESHWAR RAO;SAMAJDAR, SUSANTA;GUPTA, AJAY;REEL/FRAME:040224/0782

Effective date: 20160718

STCF Information on status: patent grant

Free format text: PATENTED CASE

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20221225